Dr. Oren Rosenberg is an infectious disease physician with a background in structural biology. His objective in this current project is to combine his clinical and basic science interests by studying the structure and function of key virulence determinants in Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis. Through a series of specific aims that use a combined structural, biochemical and genetic approach, Dr. Rosenberg will examine the role of essential components in the type VII secretion system, which is known to be critical for the virulence of Mtb. The goal is to understand mycobacterial infection better so as to aid in the design of faster, cheaper, less toxic and more effective ways to prevent and treat tuberculosis. Additionally this proposal is designed to complement Dr. Rosenberg's prior laboratory experience and provide him with the requisite technical and intellectual background in microbial pathogenesis and structural biology to function as an independent investigator. A committee of physicians and scientists will oversee Dr. Rosenberg's progression towards independence. His scientific development will also be enriched through attendance at UCSF courses in pertinent topics, several seminar series, departmental retreats and national meetings. Dr. Rosenberg will develop a clinical specialization in tuberculosis and other respiratory infections through work at the tuberculosis clinic at San Francisco General Hospital. At the end of the granting period Dr. Rosenberg will be prepared to develop his own research and clinical agenda as an independent investigator in the basic biology of microbial pathogenesis.